Crit Care Med 2009;37:1837-1844

Plasma N-terminal pro-B-type natriuretic peptide (Nt-pro-BNP) levels are frequently elevated in critically ill patients and are associated with an increased mortality. In this study, we determined Nt-pro-BNP levels in patients with cardiogenic shock (CS) and evaluated its association with clinical and hemodynamic parameters and 30-day mortality.

Design
Retrospective study.

Setting
Two, eight-bed intensive care units at a university and a community hospital.

Patients
Retrospective study on stored plasma samples of 58 patients with CS, obtained at admission to the intensive care unit.

Interventions
None.

Measurements and main results
Massively elevated Nt-pro-BNP concentrations showed no significant association with duration of shock, total Sequential Organ Failure Assessment score, or invasive hemodynamic parameters at the time of blood sampling but a significant association with estimated glomerular filtration rate (p < 0.001), C-reactive protein (p = 0.03), age (p = 0.005), and body weight (p = 0.03). Both in univariate and multivariate survival analyses, Nt-pro-BNP levels above the median (>12,782 pg/mL) were significant predictors of 30-day mortality (p < 0.001) and showed a complementary role with interleukin (IL)-6 in predicting outcome. Patients with IL-6 >195 pg/mL and Nt-pro-BNP above the median value had the highest 30-day mortality (93.7%), whereas patients with lower IL-6 levels together with lower Nt-pro-BNP levels had significantly better survival (mortality rate 26.3%). Among patients who had acute myocardial infarction, those with Nt-pro-BNP concentrations above the median level showed a highly impaired clinical course even if coronary revascularization was successful (30-day mortality 90.9% vs. 29.4%, p = 0.001), whereas survival of patients with unsuccessful revascularization did not differ significantly with respect to the median of Nt-pro-BNP (30-day survival rate 81.8% vs. 75.0%, p = 0.71).

Conclusion
The massive elevations of Nt-pro-BNP observed in the early phase of CS seem to be independent of ventricular performance. Nt-pro-BNP levels are nevertheless predictive of 30-day survival in patients with CS especially in those with successful revascularization and might be used in combination with IL-6 for estimation of outcome early on.

Intensive Care Med 2008:34;2147-2156

Patients with pulmonary embolism (PE) have a high risk of death, and it is important to recognize factors associated with higher mortality. Recently, several biomarkers have been studied for risk stratification in patients with PE.

Objectives
Evaluate the available evidence on (a) the accuracy of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) for the diagnosis of right ventricular dysfunction and (b) their value as a prognostic factor of all-cause in-hospital or short-term mortality in patients with PE.

Data sources
MEDLINE, Embase, and citation review of relevant primary and review articles.
Selection criteria  We selected studies evaluating the accuracy of BNP or NT-proBNP for the diagnosis of right ventricular dysfunction. We also selected studies that reported data on BNP or NT-proBNP as a predictor of short-term mortality in patients with PE.

Results
Sixteen studies met our inclusion criteria. The pooled diagnostic odds ratio for the diagnosis of right ventricular dysfunction in pulmonary embolism was 39.45 (95% CI; 15.54ñ100.12) and 24.73 (95% CI 2.02ñ302.37) for BNP and NT-proBNP, respectively. The pooled odds ratio for all-cause in-hospital or short-term mortality was 6 (95% CI 1.31±27.43; p: 0.021) and 16.12 (95% CI 3.1±83.68; p: 0.001) for BNP (cutoff: 100 pg/ml) and NT-proBNP (cutoff: 600 ng/L), respectively.

Conclusion
The results of this meta-analysis indicate that BNP and NT-proBNP are associated with the diagnosis of right ventricular dysfunction (RVD) in patients with an acute PE and are significant predictors of all-cause in-hospital or short-term mortality in these patients.

Critical Care 2008;12:R118

Increased serum B-type natriuretic peptide (BNP) has been identified for diagnosis and prognosis of impaired cardiac function in patients suffering from congestive heart failure, ischemic heart disease, and sepsis. However, the prognostic value of BNP in multiple injured patients developing multiple organ dysfunction syndrome (MODS) remains undetermined. Therefore, the aims of this study were to assess N-terminal pro-BNP (NT-proBNP) in multiple injured patients and to correlate the results with invasively assessed cardiac output and clinical signs of MODS.

Methods
Twenty-six multiple injured patients presenting a New Injury Severity Score of greater than 16 points were included. The MODS score was calculated on admission as well as 24, 48, and 72 hours after injury. Patients were subdivided into groups: group A showed minor signs of organ dysfunction (MODS score less than or equal to 4 points) and group B suffered from major organ dysfunction (MODS score of greater than 4 points). Venous blood (5 mL) was collected after admission and 6, 12, 24, 48, and 72 hours after injury. NT-proBNP was determined using the Elecsys proBNP® assay. The hemodynamic monitoring of cardiac index (CI) was performed using transpulmonary thermodilution.

Results
Serum NT-proBNP levels were elevated in all 26 patients. At admission, the serum NT-proBNP values were 116 ± 21 pg/mL in group A versus 209 ± 93 pg/mL in group B. NT-proBNP was significantly lower at all subsequent time points in group A in comparison with group B (P < 0.001). In contrast, the CI in group A was significantly higher than in group B at all time points (P < 0.001). Concerning MODS score and CI at 24, 48, and 72 hours after injury, an inverse correlation was found (r = -0.664, P < 0.001). Furthermore, a correlation was found comparing MODS score and serum NT-proBNP levels (r = 0.75, P < 0.0001).

Conclusions
Serum NT-proBNP levels significantly correlate with clinical signs of MODS 24 hours after multiple injury. Furthermore, a distinct correlation of serum NT-proBNP and decreased CI was found. The data of this pilot study may indicate a potential value of NT-proBNP in the diagnosis of post-traumatic cardiac impairment. However, further studies are needed to elucidate this issue.

Crit Care Med 2008;36:3030-3037

In early stages of septic shock, impaired myocardial function plays an important prognostic role. In this context, B-type natriuretic peptide (BNP) has been shown to be a neurohumoral marker for left ventricular dysfunction, because myocardial strain and ischemia both increase BNP concentration. The present study was designed to test if BNP allows for identification of patients at risk for developing sepsis-induced myocardial depression and if an increased concentration of BNP is associated with an adverse outcome in patients with septic shock.

Methods and Results
In a prospective study, 93 patients with septic shock were divided into one group with normal ventricular function (left ventricular ejection fraction >50%) on days 3 to 5 (n = 38) and another group of patients with impaired left ventricular function (left ventricular ejection fraction <50%) on days 3 to 5 (n = 55). Patients with impaired left ventricular function had an increased median plasma BNP concentration on day 5 (699 [608 of 795.5] pg/nL vs. 86 [71.3 of 93] pg/nL) and an ejection fraction of 38 +/- 6% on day 5 vs. 58 +/- 7% in patients without impaired left ventricular function. There was a close inverse relation between increased plasma BNP concentrations and depressed left ventricular ejection fraction (p < 0.05). BNP measured at days 3 and 5 revealed an association with the end point of survival. In the proportional hazards regression model adjusted for age, male gender, and creatinine concentration, measured at days 0, 3, 5, and 12, BNP concentration at day 5 showed an increased hazard for reaching the end point (hazard ratio: 1.407; 95% confidence interval: 1.033-1.916; p = 0.030). In an additional receiver operating characteristic curve analysis, the predictive value of a model including cardiovascular risk factors and additional BNP concentration on day 5, compared with a baseline model of cardiovascular risk factors, improved the area under the curve the most; therefore, this model was suited best for prediction of sepsis-induced myocardial depression and 30-day survival for patients with septic shock. Area under the curve of this model combined with BNP concentration at day 5 for death after 30 days (0.65) impaired left ventricular ejection fraction (0.94) and sepsis-induced myocardial depression (0.96).

Conclusion
These results indicate that plasma BNP concentration represents a reliable marker for identification of patients developing sepsis-induced myocardial depression. In addition, BNP concentration on day 5 may be used as a prognostic marker to identify patients with an elevated risk for an adverse outcome.

Crit Care Med 2008; 36:2542-2546

High B-type natriuretic peptide (BNP) levels are reported in the context of septic shock. We hypothesized that high BNP levels might be related to an alteration in BNP clearance pathway, namely neutral endopeptidase (NEP) 24.11. NEP 24.11 activity was measured in septic shock and in cardiogenic shock patients. We further evaluated whether baseline plasma BNP can predict fluid responsiveness and whether BNP can still be released in plasma despite high initial BNP levels, in response to overloading.

Material and Methods
Prospective observational study. Patients in severe sepsis (S) or in septic shock (SS) needing a fluid challenge were included. Stroke volume (SV) and BNP were measured before (SV1, BNP1) and 45 mins after (SV2, BNP2) a standardized fluid challenge. DeltaBNP was defined as the difference between BNP2 and BNP1. NEP 24.11 activity was determined by fluorometry in 12 SS and 4 S patients before fluid challenge and in 5 cardiogenic shock patients.

Results
Twenty-three patients (61 +/- 18 years old, Simplified Acute Physiology Score II: 54 +/- 21; 19 SS, 4 S; BNP1: 1371 +/- 1434 pg/mL) were studied. BNP1 concentrations were significantly higher in SS than in S (1643 +/- 1437 vs. 80 +/- 35 pg/mL; p = 0.002). There was no correlation between baseline BNP and fluid responsiveness. Nine of the 11 patients with BNP1 >1000 pg/mL were fluid responders. DeltaBNP was greater in fluid nonresponders than in fluid responders (22 +/- 27% vs. 6 +/- 11%, p = 0.028). Plasma BNP was higher in SS than in cardiogenic shock patients (1367 +/- 1438 vs. 750 +/- 346 respectively; p = 0.027). NEP 24.11 activity was lower in SS than in S patients (0.10 +/- 0.06 nmole/mL/min vs. 0.50 +/- 0.22 nmole/mL/min, p <0.0001) cardiogenic shock patients (0.10 +/- 0.06 nmole/mL/min vs. 0.58 +/- 0.19 nmole/mL/min; p = 0.002).

Conclusion
High levels of BNP might be related to an alteration in BNP clearance. During sepsis, high BNP levels are not predictive of fluid nonresponsiveness. Nevertheless, in fluid nonresponders, acute ventricular stretching can result in further BNP release.

Crit Care Med 2008;36:2322-2327

Patients with acute respiratory distress syndrome suffer from profound cardiac and pulmonary derangement, including right ventricular strain and noncardiogenic pulmonary edema, which may potentially alter concentrations of cardiac natriuretic peptides. We sought to determine whether N-terminal probrain natriuretic peptide (NT-proBNP) levels are elevated in acute respiratory distress syndrome and whether they can serve as a marker of prognosis in this setting.

Design
Prospective study.

Setting
Tertiary-care academic medical center.

Patients
One hundred seventy-seven acute respiratory distress syndrome subjects enrolled in a prospective intensive care unit cohort.

Interventions
None

Measurements and main results
NT-proBNP was measured from blood taken within 48 hrs of acute respiratory distress syndrome onset. Patients were followed for the primary outcome of 60-day mortality and secondary outcomes of organ dysfunction and ventilator-free days. Seventy patients died (40%). Median NT-proBNP level was 3181 ng/L (interquartile range 723-9246 ng/L). NT-proBNP levels were significantly higher among nonsurvivors (p < .0001). Receiver operating curve analysis revealed an optimal NT-proBNP cut-point of 6813 ng/L for predicting death. Patients with levels above the cut-point had significantly higher odds of mortality on multivariable analysis (odds ratio 2.36, 95% confidence interval 1.11-4.99, p = .02) than those with levels below the cut-point. Kaplan-Meier survival analysis showed that this difference emerged early and was sustained (p < .0001). Patients with elevated NT-proBNP also had higher organ dysfunction scores (p < .0001) and fewer ventilator free days (p = .03) than those with lower NT-proBNP levels.

Conclusions
NT-proBNP levels are elevated among acute respiratory distress syndrome patients and parallel the severity of the syndrome and likelihood for morbidity and mortality. This demonstrates the potential utility of this biomarker for prognosis in this disease.

Critical Care 2008;12:R109

The relationship between brain natriuretic peptide (BNP) increase in acute pulmonary embolism (PE) and the increase in mortality and morbidity has frequently been suggested in small studies but its global prognostic performance remains largely undefined. We performed a systematic review and meta-analysis of data to examine the prognostic value of elevated BNP for short term all-cause mortality and serious adverse events.

Methods
The authors reviewed PubMed, BioMedCentral, and the Cochrane database and conducted a manual review of article bibliographies. Using a prespecified search strategy, we included a study if it used BNP or N-Terminal Pro-Brain Natriuretic Peptide (NT-pro BNP) biomarkers as a diagnostic test in patients with documented pulmonary embolism and if it reported death, the primary endpoint of the meta-analysis, in relation to BNP testing. Studies were excluded if they were performed in patients without certitude of PE or in a subset of patients with cardiogenic shock. Twelve relevant studies involving a total of 868 patients with acute PE at baseline were included in the meta-analysis using a random-effects model.

Results
Elevated BNP levels were significantly associated with short-term all-cause mortality (odds ratio [OR], 6.57; 95% confidence interval (CI), 3.11 to 13.91), with death resulting from pulmonary embolism (OR, 6.10; 95% CI, 2.58 to 14.25), and with serious adverse events (OR, 7.47; 95% CI, 4.20 to 13.15). The corresponding positive and negative predictive values for death were 14% (95%, 11 to 18) and 99% (95% CI, 97 to 100), respectively.

Conclusions
This meta-analysis indicates that while elevated BNP levels can help to identify patients with acute pulmonary embolism at high risk of death and adverse outcome events, the high negative predictive value of normal BNP levels is certainly more useful for clinicians to select patients with a likely uneventful follow-up.

Anaesthesia 2008;63:482-487

Heart failure is a major risk factor for adverse postoperative events following non-cardiac surgery. The use of transthoracic echocardiogram as a pre-operative investigation to assess cardiac dysfunction has limitations in this setting. The N-Terminal fragment of B-Type natriuretic peptide (NT proBNP) has been used in screening for heart failure. We have investigated the use of NT proBNP as a screening tool for left ventricular systolic dysfunction to reduce the requirement for pre-operative echocardiograms. Ninety-eight pre-operative non-cardiac surgical patients scheduled to undergo echocardiography were assessed clinically and with an NT proBNP measurement. Echocardiogram was used to define two groups of patients depending on the presence or absence of abnormal left ventricular function and the NT proBNP level was compared between the groups using non-parametric and receiver-operator-characteristic (ROC) curve analysis. In terms of pre-operative screening, a NT proBNP of <38.2 pmol.l⁻¹ had a 100% negative predictive value in predicting patients with normal left ventricular systolic function and would have prevented the requirement for echocardiogram in 43% of pre-operative patients. NT proBNP was superior to electrocardiological and clinical criteria for detection of a normal echocardiogram. This may have significant impact in the pre-operative assessment of patients undergoing non-cardiac surgery.

Crit Care Med 2007;35:2438-2439

B-type natriuretic peptides (BNP and NT-pro-BNP) are quantitative markers of cardiac stress and heart failure, summarizing the extent of systolic and diastolic left ventricular dysfunction, valvular dysfunction, and right ventricular dysfunction. They have been shown to be extremely helpful in the diagnosis and prognosis of heart failure, particularly in the emergency department. As the diagnostic dilemmas in the intensive care unit (ICU) are often as challenging as in the emergency department, recent studies have begun to evaluate whether the use of BNP might also be helpful in the ICU. Major differences in patient characteristics, disease severity, comorbidity, resources available for the individual patient, and therapies applied between the ICU and the emergency department require that the potential clinical use of BNP in the ICU be defined by specific ICU studies.

The use of a biomarker to detect heart failure in the ICU is based on the observation that heart failure is common in the ICU and on the assumption that the detection of heart failure in the ICU allows the initiation of specific heart failure therapy or changes in patient management that ultimately might improve patient morbidity and mortality. In critically ill patients, even small improvements in management might have the potential to improve patient outcome.

Natriuretic peptides emerged during recent years as potent prognostic markers in patients with heart failure and acute myocardial infarction. In addition, natriuretic peptides show strong predictive value in patients with pulmonary embolism, sepsis, renal failure, and shock. The present study tests the prognostic information of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) in an unselected cohort of critically ill patients.

Design
Prospective, observational study.

Setting
A tertiary intensive care unit in a university hospital.

Patients
A total of 289 consecutive patients admitted to the intensive care unit during a 16-month period with the following data: age 64 +/- 14 yrs, male n = 191, Simplified Acute Physiology Score II of 52 +/- 24, mechanical ventilation n = 180 (62%), vasopressors n = 179 (62%), renal failure n = 24 (8%).

Interventions
None.

Measurements and Main Results
Plasma NT-pro-BNP samples (Roche Diagnostics) were obtained on intensive care unit admission. Data are given as median [range]. Intensive care unit survivors had significantly lower NT-pro-BNP values compared with intensive care unit nonsurvivors (3394 [24-35,000] vs. 6776 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). Hospital survivors were characterized by significantly lower NT-pro-BNP values (2656 [24-35,000] vs. 8390 [303-35,000] pg/mL, survivors vs. nonsurvivors, respectively, p = .001). NT-pro-BNP levels were not significantly different in patients with primary cardiac diagnosis compared with those with a noncardiac admission diagnosis (4794 [26-35,000], n = 202 vs. 3349 [24-35,000], n = 87, cardiac vs. noncardiac, respectively, p = .28). In a logistic regression model, Simplified Acute Physiology Score II and NT-pro-BNP were independently associated with hospital survival ([chi]2 = 35.6, p = .0001 and [chi]2 = 11.3, p = .0008, Simplified Acute Physiology Score II and NT-pro-BNP, respectively). Areas under the receiver operating characteristic curves of NT-pro-BNP and Simplified Acute Physiology Score II were not statistically significant different regarding the prediction of outcome.

Conclusions
NT-pro-BNP on admission is an independent prognostic marker of outcome in an unselected cohort of critically ill patients. A single measurement of NT-pro-BNP might facilitate triage of emergency and intensive care unit patients.

Anaesthesia 2007;62:875–881

B-type natriuretic peptide (BNP) levels predict cardiovascular risk in several settings. We hypothesised that they would identify individuals at increased risk of complications and mortality following major emergency non-cardiac surgery. Forty patients were studied with a primary end-point of a new postoperative cardiac event, and/or development of significant ECG changes, and/or cardiac death. The main secondary outcome was all-cause mortality at 6 months. Pre-operative BNP levels were higher in 11 patients who suffered a new postoperative cardiac event (p = 0.001) and predicted this outcome with an area under the receiver operating characteristic curve of 0.85 (CI = 0.72–0.98, p = 0.001). A pre-operative BNP value > 170 pg.ml^-1 has a sensitivity of 82% and a specificity of 79% for the primary end-point. In this small study, pre-operative BNP levels identify patients undergoing major emergency non-cardiac surgery who are at increased risk of early postoperative cardiac events. Larger studies are required to confirm these data.

British Journal of Anaesthesia 2007;99:170-176

B-type natriuretic peptide (BNP) levels predict cardiovascular risk in several settings. We hypothesized that they would identify individuals at increased risk of early cardiac complications after major non-cardiac surgery. The current study tests this hypothesis.

Methods
Two hundred and four patients undergoing major non-cardiac surgery were studied. The primary end-point was the development of acute myocardial injury [defined as cardiac troponin I (cTnI) level > 0.32 ng ml^–1] or death in the 3 days after surgery.

Results
Preoperative BNP levels were raised in patients who died or suffered perioperative myocardial injury (median 52.2 vs 22.2 pg ml^–1, P = 0.01) and BNP predicted this outcome with an area under the receiver operating characteristic curve of 0.72 [95% confidence interval (CI) 0.59–0.86, P = 0.01]. A preoperative BNP value > 40 pg ml^–1 was associated with an increased risk of death or perioperative myocardial injury [odds ratio (OR) 6.8, 95% CI 1.8–25.9, P = 0.003], and remained independently predictive after correction for the Revised Cardiac Risk Index. Preoperative BNP levels were higher in patients who exhibited new onset atrial fibrillation or ST/T-wave changes on their postoperative ECG (median 50.5 vs 22.5 pg litre^–1, P = 0.01). They were also higher in patients who had either elevation of cTnI > 0.32 ng ml^–1 or postoperative ECG abnormalities (median 50.4 vs 21.5 pg ml^–1, P < 0.001).

Conclusions
In the setting of major non-cardiac surgery, preoperative BNP levels are higher in patients who experience perioperative death and myocardial injury. Larger studies are required to confirm these data and to clarify what BNP levels may add to existing methods of risk stratification.

British Journal of Anaesthesia 2007;99:151-154

There is presently much interest in the preoperative identification of high-risk patients undergoing major surgery—with the aim of adopting management strategies which may reduce postoperative morbidity and mortality. In the non-cardiac surgical patient, data for the UK suggest that there may be up to 8000 cardiovascular deaths per year for 5 million surgical procedures performed, with an incidence of 10 times that with regard to morbidity (myocardial infarction, congestive cardiac failure, malignant arrhythmias, and cardiac arrest). The major pathological disorder responsible for these adverse outcomes is ischaemic heart disease, either overt or covert, secondary to atherosclerosis. We, and others, have recently reviewed the role of biomarkers in the identification of at-risk cardiac patients.

For a test to be useful as a biomarker, it should to be able to differentiate between the ‘healthy’ and the ‘compromised’ patient. In epidemiological terms, it needs to have a high sensitivity (probability that the biomarker….